Can Protein Folding be p0wned?

Are you a l33t gamer? Can you r0x0r the tertiary structure? If so, you might be interested in FoldIt, a new “online” game which essentially strives to create a chimera of computer program and human to solve tertiary structure problems in novel proteins. As described at MIT Technology Review today:

For years, biochemists have reengineered naturally occurring proteins by growing them in viruses and single-celled organisms in a process called directed evolution. But researchers need to start with a preexisting protein, which makes it difficult to develop proteins with totally new functions. In a major step forward, Baker recently demonstrated the first algorithm for building novel, functioning enzymes from scratch. But while proteins built from the ground up may have chemical properties unmatched by anything in nature, they aren’t particularly efficient.

The game, called Foldit, is part of Baker’s vision for the future of protein engineering. His algorithms are good at the nitty-gritty of generating completely novel protein sequences for a particular purpose. But humans, who are better at seeing the big picture than computers are, could improve computer-designed proteins by playing the game.

Proteins are made up of long strings of amino acids that are folded up into complex three-dimensional tangles with many subregions. The function of a protein is dependent on this three-dimensional structure. One pocket might be ideal for grabbing on to another protein, for example. Other parts of the protein may play a purely supportive, structural role, holding the molecule together. Baker’s new method for creating novel proteins begins with the active sites. Once they’re in place, structural concerns, especially how tightly packed the protein is, determine whether the design is feasible. Figuring out the best way to hold together the active sites is a complicated search problem that requires a lot of processing power. There are a myriad of possibilities, but most won’t work.

The “online” part is a little dubious, since the game is essentially played locally on your PC or Mac. It requires installing a 50+MB executable. The player begins with some tutorial levels, which ease the person into learning and utilizing the both the manual manipulations and automatic tools available to achieve tertiary structures which are feasible and optimized. The interface is done well, the controls are fairly intuitive and unobtrusive, and the user is rewarded at each success. You cannot aspire to obtain the Sword of a Thousand Truths, perhaps, but you might achieve some serious RL impact, if the game fulfills the goals of it’s creators.

Protein folding problems, in general, are difficult, if not downright impossible, to solve with merely computational means. There is no elegant and efficacious algorithm to solve these problems, as the About page affirms:

Protein structure prediction: As described above, knowing the structure of a protein is key to understanding how it works and to targetting it with drugs. A small proteins can consist of 100 amino acids, while some human proteins can be huge (1000 amino acids). The number of different ways even a small protein can fold is astronomical because there are so many degrees of freedom. Figuring out which of the many, many possible structures is the best one is regarded as one of the hardest problems in biology today and current methods take a lot of money and time, even for computers. Foldit attempts to predict the structure of a protein by taking advantage of humans’ puzzle-solving intuituions and having people play competitively to fold the best proteins.

FoldIt also states that in the coming months, users will not only be able to modify proteins existing in the game, but also be able to design their own proteins.

To paraphrase an old gamer quote: All your active sites are belong to us!

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